Hypercalcemia 

Hypercalcemia can result when too much calcium (Ca) enters the extracellular fluid (ECF) or when there is insufficient calcium excretion from the kidneys.

Calcium plays an important role in intracellular and extracellular metabolism controlling such processes as nerve conduction, muscle contraction, coagulation, electrolyte and enzyme regulation, and hormone release. Calcium metabolism, in turn, is tightly regulated by a series of hormones that affect not only the entry of calcium into the extracellular space from bone and the GI tract but also control its excretion from the kidneys.

Calcium hemostasis

Ninety-eight percent of body calcium is found in the skeleton; this is closely related to the extracellular concentration of calcium. Intracellular calcium is less than extracellular calcium by a factor of 100,000. Intracellular processes, including the activity of many enzymes, cell division, and exocytosis, are controlled by intracellular calcium. The primary mediator of the intracellular effects of calcium is the calcium-binding regulatory protein, calmodulin.

Plasma calcium is maintained despite its large movements across the gut, bone, kidney, and cells. Changes in calcium ions usually are accompanied by changes in total calcium in the ECF. In plasma, calcium exists in 3 different forms: (1) 50% as ionized or the biologically active form, (2) 45% bound to plasma proteins (mainly albumin), and (3) 5% complexed to phosphate and citrate. Because the proportion of bound calcium varies little within individuals, in the absence of severe acidosis or alkalosis, the amount of albumin is the major factor determining the amount of calcium that is bound.

Very little evidence suggests that intracellular stores of calcium contribute in any way to plasma calcium homeostasis. An exception is in the parathyroid gland, in which the intracellular concentration increases in response to changes in extracellular concentration, which in turn alters the rate of parathyroid hormone (PTH) secretion. Any decrease in extracellular calcium ion concentration leads to an increase in PTH secretion. PTH increases distal renal tubular reabsorption of calcium within minutes and stimulates osteoclast activity, with release of calcium from the skeleton within 1-2 hours. More prolonged PTH elevation stimulates 1alpha-hydroxylase activity in the proximal tubular cells, which leads to 1,25-dihydroxyvitamin D (1,25(OH)2 D3) production. All these mechanisms help to maintain the serum calcium level within normal limits.

A normal serum calcium level is 8-10 mg/dL (2-2.5 mmol/L) with some interlaboratory variation in the reference range, and hypercalcemia is defined as a serum calcium level greater than 10.5 mg/dL (>2.5 mmol/L). Hypercalcemia may be classified based on total serum and ionized calcium levels, as follows:

• Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or Ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L)
• Moderate: Total Ca 12-13.9 mg/dL (3-3.5 mmol/L) or Ionized Ca 5.6-8 mg/dL (2-2.5 mmol/L)
• Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or Ionized Ca 10-12 mg/dL (2.5-3 mmol/L)

Only 1-2% of total body calcium is in the exchangeable form in circulation, and the rest forms part of the skeleton. Only one half of the exchangeable calcium is in the active ionized form with the remainder bound to albumin, globulin, and other inorganic molecules. Protein binding of calcium is influenced by pH with metabolic acidosis leading to increased ionized calcium from reduced protein binding, and alkalosis leading to reduced ionized calcium from increased protein binding. Because calcium binds to albumin and only the unbound (free or ionized) calcium is biologically active, the serum level must be adjusted for abnormal albumin levels.

For every 1-g/dL drop in serum albumin below 4 g/dL, measured serum calcium decreases by 0.8 mg/dL. Therefore, to correct for an albumin level of less than 4 g/dL, one should add 0.8 to the measured value of calcium for each 1-g/dL decrease in albumin. Without this correction, an abnormally high serum calcium level may appear to be normal.

A patient with a serum calcium level of 10.3 mg/dL but an albumin level of 3 g/dL appears to have a normal serum calcium level. However, when corrected for the low albumin, the real serum calcium value is 11.1 mg/dL (10.3 + 0.8), a more obviously abnormal level. Alternatively, serum free (ionized) calcium levels can be directly measured, negating the need for correction for albumin. Corrected calcium can be calculated using the following formula:

Corrected Ca = ([4 - plasma albumin in g/dL] X 0.8 + serum calcium)

Mild cases of hypercalcemia can be asymptomatic and are more often diagnosed incidentally from routine blood tests. Because calcium metabolism normally is tightly controlled by the body, even mild persistent elevations above normal signal disease and should be investigated.

Calcium is controlled by 2 mechanisms. These are (1) controlling or major regulatory hormones and (2) influencing hormones. Controlling or major regulatory hormones include PTH, calcitonin, and vitamin D. The image below reviews vitamin D metabolism. In the kidney, vitamin D and PTH stimulate the activity of the epithelial calcium channel and the calcium-binding protein (ie, calbindin) to increase active transcellular calcium absorption in the distal convoluted tubule. Influencing hormones include thyroid hormones, growth hormone, and adrenal and gonadal steroids.

Role of the calcium-sensing receptor

The calcium-sensing receptor (CaSR) is a G protein–coupled receptor, which allows the parathyroid chief cells, the thyroidal C cells, and the ascending limb of the loop of Henle (renal tubular epithelial cells) to respond to changes in the extracellular calcium concentration. The ability of the CaSR to sense the serum Ca⁺⁺ is essential for the appropriate regulation of PTH secretion by the parathyroid glands and for the regulation of passive paracellular calcium absorption in the loop of Henle. Calcitonin secretion and renal tubular calcium reabsorption also are directly regulated by the action of Ca⁺⁺ on the calcium receptor.^[1]

The CaSR gene is located on band 3q13-q21 and encodes a 1078 amino acid protein. CaSR is expressed in many tissues. Three uncommon human disorders are due to abnormalities of the CaSR gene, (1) familial benign hypocalciuric hypercalcemia, (2) neonatal severe hyperparathyroidism, and (3) autosomal dominant hypocalcemia with hypercalciuria.^{[2, 3]}

Recent studies

In a study of 90 patients with advanced head and neck squamous cell carcinoma (HNSCC), Alsirafy et al compared outcomes for those patients in the cohort who had hypercalcemia (46 patients) with those of patients who did not. The authors found that compared with nonhypercalcemic inpatients, inpatients with hypercalcemia had a higher rate of palliative care referrals. Moreover, during the final 3 months of patient follow-up, a greater percentage of individuals with hypercalcemia paid more than 1 visit to the emergency room and a larger proportion of hypercalcemic patients were hospitalized for at least 14 days.

The authors also determined that among the study's patients who were referred for palliative care, the median postreferral survival time for those with hypercalcemia was 43 days, while that for nonhypercalcemic patients was 128 days. Alsirafy et al concluded that if hypercalcemia in patients with HNSCC is detected and managed early, this may help to prevent hypercalcemia-associated symptoms and to reduce hospitalization time.^[4]

Hypercalcemia affects nearly every organ system in the body, but it particularly affects the CNS and kidneys. Mild hypercalcemia may not produce any symptoms. With modest hypercalcemia, most patients begin to feel fatigued. With higher levels, patients may have anxiety, depression, personality changes, and confusion. With very high levels, somnolence, coma, and death may ensue. The CNS effects are thought to be due to the direct depressant effect of hypercalcemia.

Renal effects include nephrolithiasis from the hypercalciuria. Distal renal tubular acidosis may be observed, and the increase in urine pH and hypocitraturia also may contribute to stone disease. Nephrogenic diabetes insipidus occurs from medullary calcium deposition and inhibition of aquaporin-2, the arginine-vasopressin–regulated water channel. Renal function may decrease due to hypercalcemia-induced renal vasoconstriction or if hypercalcemia is prolonged from calcium deposition (nephrocalcinosis) and interstitial renal disease.

High calcium levels also affect the conducting system of the heart and cause cardiac arrhythmias. Calcium has a positive inotropic effect. Hypercalcemia also causes hypertension, presumably from renal dysfunction and direct vasoconstriction.

The GI manifestations of hypercalcemia include anorexia, nausea, vomiting, and constipation. Prolonged hypercalcemia tends to cause high gastrin levels, which may contribute to peptic ulcer disease and may lead to pancreatitis or the deposition of calcium in any soft tissue. This deposition of calcium is especially prevalent if phosphorous levels also are elevated, as in renal failure.

The severity of symptoms is related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred. Serum calcium levels greater than approximately 15 mg/dL usually are considered to be a medical emergency and must be treated aggressively.

Frequency

United States

Hypercalcemia is relatively common and often is mild but of long duration. The incidence of hyperparathyroidism alone is approximately 1-2 cases per 1000 adults. Mild cases are often not diagnosed.

International

Screenings of large groups of patients have found prevalence rates as high as 39 cases per 1000 persons in Scandinavia. Similar screenings in South Africa showed a prevalence of 8 cases per 1000 persons. These higher incidences may reflect underdiagnosis in the United States rather than a true difference in prevalence.

Mortality/Morbidity

Morbidity and mortality from hypercalcemia depend entirely on the cause.

• Hypercalcemia from hyperparathyroidism tends to be mild and prolonged. Morbidity is related to the resultant bone disease. Because this condition is underdiagnosed so often, actual morbidity is unknown. Mild hypercalcemia rarely, if ever, leads directly to death.
• Hypercalcemia caused by a neoplasm tends to be much more serious. The mechanism of hypercalcemia in malignancy can be from the ectopic production of a PTH-like factor, PTH-related protein (PTHrP), or osteolytic metastases. Often, the hypercalcemia is the immediate cause of death in patients with ectopic PTHrP production. These patients rarely survive more than a few weeks or months. Osteolytic metastases tend to cause morbidity and mortality from nerve compression and other orthopedic complications. These patients may live longer but still have a poor prognosis, especially if their serum calcium levels are very high.
• Morbidity and mortality associated with hypercalcemia from other causes are directly related to the underlying cause and tend to be less serious. In these patients, hypercalcemia is a reflection of their disease state and morbidity and mortality depend on control of the underlying disease.

Sex

Some studies show a higher incidence in men compared to women, but this difference tends to diminish with increasing age. One study found the highest incidence to be in women aged 60-63 years.

Age

Hypercalcemia from nearly all causes increases with advancing age, especially the 2 most common causes, malignancy and hyperparathyroidism. However, hypercalcemia may occur in persons of any age.